Multi-Omics Correlates of Broadly Neutralizing Antibody Efficacy

广泛中和抗体功效的多组学关联

• 批准号: 10724224
• 负责人: Dan H. Barouch
• 金额: $ 23.25万
• 依托单位: BETH ISRAEL DEACONESS MEDICAL CENTER
• 依托单位国家: 美国
• 财政年份: 2023
• 资助国家: 美国
• 起止时间: 2023-07-11 至 2028-04-30
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/10724224
• 关键词: Antibody Therapy; Cell surface; Cells; Cellular Immunity; Cellular Indexing of Transcriptomes and Epitopes by Sequencing; Chromatin; Clinical; Clinical Trials; Computer Analysis; Data; Dose; Drug Kinetics; Effectiveness; Genetic Transcription; Genomics; HIV-1; Human; Immune response; Immunologics; In Situ; Individual; Infusion procedures; Intervention Studies; Lymphoid Tissue; Macaca; Macaca mulatta; Measures; Molecular Profiling; Mucous Membrane; Multiomic Data; Participant; Phenotype; Property; Proteins; Proteomics; Reporting; Resistance; Resolution; Specimen; Testing; Therapeutic; Tissue Sample; Tissues; Transcript; Vaccine Therapy; Vaccines; Viral; Viral Physiology; Viral reservoir; Virus; Virus Replication; anti-viral efficacy; gastrointestinal; insight; lymph nodes; multiple omics; neutralizing antibody; next generation; nonhuman primate; protein biomarkers; simian human immunodeficiency virus; single-cell RNA sequencing; transcriptomics; viral DNA; viral RNA; viral detection; viral rebound

SUMMARY Accumulating data suggests that administration of broadly neutralizing antibodies (bNAbs) in ART-suppressed, SHIV-infected nonhuman primates (NHPs) and HIV-1-infected humans can delay viral rebound following ART discontinuation. However, the mechanism underlying the efficacy of bNAbs remains to be determined. Multiple mechanisms may contribute to the effectiveness of bNAbs in delaying viral rebound, including direct antiviral activity against replicating virus, targeting of the replication-competent viral reservoir, and indirect effects such as augmenting cellular immune responses via the “vaccinal” effect. Understanding the mechanism of action underlying bNAb efficacy will lead to optimization of these and other HIV-1 cure strategies. In Project 1, we hypothesize that bNAbs can directly target the viral reservoir in addition to providing direct antiviral effects, both of which contribute to the observed long-term virologic control following ART discontinuation. An alternative hypothesis is that bNAbs contribute to long-term antiviral efficacy by modulating host cellular immunity via the vaccinal effect. To evaluate these hypotheses, we propose two Specific Aims: Aim 1. To determine multi-omics correlates of bNAb based virologic control in HIV-1-infected humans. We will perform a comprehensive virologic, immunologic, and multi-omics analysis of existing clinical specimens from the T003 study to generate hypotheses regarding correlates of long term vs. short term virologic control. Aim 2. To define mechanisms of bNAb efficacy in lymphoid tissues in SHIV-infected rhesus macaques. We will perform interventional studies to test the hypothesis that bNAbs can target the viral reservoir in lymph nodes and gastrointestinal mucosa in SHIV-infected rhesus macaques. We will apply cutting-edge, high-throughput, multi-omics profiling platforms detailed in Core B (Multi-Omics Core) to define the impact of bNAb therapy. We will then integrate the multi-omics data in Core C (Computational Analysis Core) to generate a comprehensive landscape and regulatory network of the viral reservoir and host immune responses following bNAb therapy. These data will define the impact of bNAbs on the replication- competent viral reservoir at an unprecedented level of resolution, which will provide critical insights for next generation HIV-1 cure efforts.

概括 累积数据表明，在ART抑制的Art抑制的抗体（BNAB）中给药， Shiv感染的非人类灵长类动物（NHP）和HIV-1感染的人可以在ART后延迟病毒反弹 中断。但是，BNAB效率的基础机制仍有待确定。多种的 机制可能有助于BNAB在延迟病毒反弹方面的有效性，包括直接抗病毒 反对复制病毒的活性，靶向复制能力的病毒储存库以及间接效应 作为通过“疫苗”效应增强细胞免疫反应。了解行动机理 基本的BNAB效率将导致这些HIV-1治疗策略的优化。 在项目1中，我们假设BNAB可以直接针对病毒储存剂，此外还可以提供 直接抗病毒作用，两者都有助于观察到的长期病毒学控制 艺术中断。另一种假设是BNAB有助于长期抗病毒效率 通过通过疫苗效应调节宿主细胞免疫。为了评估这些假设，我们提出了 两个具体的目标： 目的1。确定基于BNAB的HIV-1感染人的基于BNAB的病毒学控制的多词相关性。 我们将对现有的临床标本进行全面的病毒学，免疫和多词分析 从T003的研究中产生有关长期与短期病毒控制相关性的假设。 目的2。定义Shiv感染的恒河猕猴中淋巴组织中BNAB效率的机制。 我们将进行介入研究，以测试BNAB可以靶向淋巴病毒储量的假设 Shiv感染的恒河猕猴中的节点和胃肠道粘膜。 我们将采用核心B（多词）中详细介绍的尖端，高通量的多摩斯分析平台 核心）定义BNAB治疗的影响。然后，我们将在核心C中集成多摩斯数据（计算 分析核心）生成病毒储层和宿主的全面景观和监管网络 BNAB治疗后的免疫反应。这些数据将定义BNAB对复制的影响 - 在空前的解决方案水平上有能力的病毒储存库，这将为下一个提供关键见解 HIV-1一代治疗努力。